THIS invention relates to the preparation of a platinum(II) complexes containing a neutral bidentate ligand, such as cis-oxalato(trans-l-1,2-cyclohexanediamine)platinum(II) (also known as oxaliplatin), which has become increasingly important due to its anti-cancer activity.
Dicarboxylatoplatinum(II) complexes (such as oxaliplatin) containing a neutral bidentate ligand (“non-leaving group”) have in the past been synthesized by way of a process that utilizes a silver salt to remove halide ions from the complex. The use of a silver compound in the process results in numerous contaminants, which must be removed by further processes in order to achieve purity that is suitable for anti-cancer pharmaceutical agent purposes.
Oxaliplatin and its pharmaceutical properties were first disclosed by Kidani et al. in J Med Chem, 1978, 21, 13135 and in U.S. Pat. No. 4,169,846. In this patent a halogenoplatinum compound is used as the starting material. Halide ions are removed by a silver salt, whereafter an oxalate is introduced, either as the free acid or a salt thereof.
In general, a method for the production of oxaliplatin is as set out below:
Step 1.1 mol K2PtX4+1 mol L→PtLX2 X=Cl, Br, I and L=trans-l-1,2-diaminocyclohexane
Step 2.1 mol PtLX2+2 mol AgNO3→PtL(H2O)22++2AgX+2NO3−or1 mol PtLX2+1 mol Ag2Y→PtL(H2O)22++2AgX+Y2−Y=SO42−
Step 3.PtL(H2O)22++Z2(oxalate)→PtL(oxalate)+2Z+Z=K+, Na+ or H+
U.S. Pat. No. 5,290,961 in the name of Tanaka Kikinzoku Kogyo K.K. teaches that the abovementioned method has the disadvantage that many impurities are incorporated into the products. These impurities include unreacted PtLX2, AgX and Ag+. The presence of PtLX2 is attributed to its generally insoluble nature in water. As a result, large quantities of water must be used in step 2 to dissolve PtLX2. This prevents the AgX, even though it is insoluble in water, from being completely removed from the solution. U.S. Pat. Nos. 5,338,874 and 5,420,319, also in the name of Tanaka Kikinzoku Kogyo K.K., teach processes for the production of cis-oxalato(trans-l-1,2-diaminocyclohexane)platinum(II) with high optical purity which can be used as an active pharmaceutical ingredient of a carcinostatic agent. However, these processes also follow complicated multi-step pathways, making use of silver compounds which must also ultimately be removed from the process.